(a) Field of the Invention
This invention relates to a process for preparing 5-fluoroprostacyclins that are useful for the treatment of platelet dysfunction. More particularly, this invention relates to a process for preparing 5-fluoroprostacycylins.
The prototypical prostacyclin, an organic compound related to prostaglandins, is (5Z)-9-deoxy-6,9.alpha.-epoxy-.DELTA..sup.5 -PGF.sub.1.alpha.. See, for example, R. A. Johnson et al, J. Am. Chem. Soc., 99, 4182 (1977); R. A. Johnson et al., Prostaglandins, 12, 915 (1976); C. Pace-Asciak and L. S. Wolfe, Biochemistry, 10, 3657 (1971). Other related cyclic prostaglandins are generally collectively referred to as "prostacyclins." Prostaglandins and prostacyclins elicit a number of biological responses and typically are very potent in doing so. Among these biological effects are inhibition of blood platelet aggregation; stimulation of smooth muscle; inhibition of gastric secretion; cytoprotection of the gastric mucosa; and reduction of gastrointestinal effects of systemic administration of prostaglandin synthetase inhibitors.
(b) Prior Art
Methods for preparing various fluorinated prostacyclins are extensively reviewed by William E. Barnette in "The Synthesis and Biology of Fluorinated Prostacyclins," CRC Critical Reviews in Biochemistry, 15, 201-235 (1984). The method described in this invention is not, however, disclosed in the review. U.S. Pat. No. 4,324,730 discloses 6,9.alpha.-epoxy-5-fluoro-11.alpha.,15S-dihydroxyprosta-5E,13E-dien-1-oic acid (compare Formulas XVI and XVII of Scheme E, below), but does not describe the properties of the compound nor a specific operative method of preparation.
European Patent Application (Publication No. 062303, Oct. 13, 1982), assigned to the assignee of this invention, discloses 5-fluoroprostacyclins, including 5,6- or 6,7-unsaturated derivatives of the formulas ##STR1## A process for their preparation is disclosed utilizing the reaction of PGI.sub.2 methyl ester starting material with a fluorinating agent, preferably perchloryl fluoride, in a protic solvent, such as methanol. The resultant 5-fluoro-6-methoxy-PGI.sub.1 methyl ester represents a previously unknown key intermediate from which the valuable .DELTA..sup.5 -5-fluoro- and .DELTA..sup.6,7 -5-fluoroprostacyclins described are prepared. The foregoing published application does not specifically disclose the sterochemistry of the 5-position fluoro group nor methods for obtaining individual isomers.